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Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone based Chlamydia trachomatis inhibitors
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.ORCID-id: 0000-0001-7680-0918
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
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2019 (Engelska)Ingår i: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 10, nr 11, s. 1966-1987Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Chlamydia trachomatis infections are a global health problem and new approaches to treat C. trachomatis with drugs of high specificity would be valuable. A library of substituted ring fused 2-pyridones has been synthesized and evaluated for their ability to attenuate C. trachomatis infectivity. In vivo pharmacokinetic studies were performed, with the best candidates demonstrating that a C8-methylsulfonamide substituent improved pharmacokinetic properties important for oral administration. C8-Methyl sulfonamide analogue 30 inhibited C. trachomatis infectivity in low micromolar concentrations. Further pharmacokinetic evaluation at an oral dose of 10 mg kg(-1) showed an apparent bioavailability of 41%, compared to C8-cyclopropyl and -methoxy analogues which had negligible oral uptake. In vitro ADME (absorption, distribution, metabolism and excretion) testing of solubility and Caco-2 cell permeability revealed that both solubility and permeability is greatly improved with the C8-methyl sulfonamide 30, effectively moving it from BCS (Biopharmaceutical Classification System) class IV to II.

Ort, förlag, år, upplaga, sidor
Royal Society of Chemistry, 2019. Vol. 10, nr 11, s. 1966-1987
Nationell ämneskategori
Farmaceutiska vetenskaper
Identifikatorer
URN: urn:nbn:se:umu:diva-166479DOI: 10.1039/c9md00405jISI: 000498725400013Scopus ID: 2-s2.0-85075072755OAI: oai:DiVA.org:umu-166479DiVA, id: diva2:1382129
Forskningsfinansiär
CancerfondenKnut och Alice Wallenbergs StiftelseGöran Gustafssons stiftelse för naturvetenskaplig och medicinsk forskning (KVA)KempestiftelsernaStiftelsen för strategisk forskning (SSF)Tillgänglig från: 2020-01-02 Skapad: 2020-01-02 Senast uppdaterad: 2023-08-25Bibliografiskt granskad
Ingår i avhandling
1. Novel inhibitors of Chlamydia trachomatis virulence
Öppna denna publikation i ny flik eller fönster >>Novel inhibitors of Chlamydia trachomatis virulence
2020 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Chlamydia trachomatis is an obligate intracellular bacterium that infects over 100 million people globally every year. Chlamydia infections can be persistent, cause infertility and blindness, adding an economical burden in the healthcare systems. Moreover, Chlamydia infections are treated with broad-spectrum antibiotics that contribute to the selection of antibiotic resistant bacteria in the commensal flora. For this reason, novel compounds with specificity against C. trachomatis would be important for treatment of Chlamydia infections.

We have developed a new class of substituted 2-pyridone amides that inhibited development of C. trachomatis. While bacterial growth was only affected to a limited extent, the produced progeny bacteria had impaired capacity to infect new cells. The compounds presented no toxicity in human or mouse cell lines and they did not inhibit growth of bacteria from the normal flora. Structure activity relationship (SAR) development of 2-pyridones lead to compounds with effect at nanomolar concentrations. Further modifications of the C3 part of the molecules resulted in isostere compounds with even a higher potency. By exploring the C8 position, we observed that methylsulfonamide substituents improved the pharmacokinetic properties and enabled oral uptake in mice. This discovery opens the door for oral treatment.

Among 2-pyridone amides, KSK213 was one of the most potent and we investigated the mode of action on the life cycle of C. trachomatis. KSK213 reduced transcription by the end of the developmental cycle and upon infection of new host cells. Mutations in RNA helicase and RNAse III genes, involved in transcription, mediated resistance to KSK213. It also attenuated the infectivity in a mouse vaginal infection model. To further explore the molecular target for 2-pyridone amides in Chlamydia, we used a custom synthesized probe for affinity chromatography approaches.

Here we show that 2-pyridones are potent non-toxic inhibitors of C. trachomatis that can be chemically modified to increase potency and enable oral bioavailability. These molecules have the potential to treat and prevent Chlamydia infections without affecting the normal flora.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2020. s. 48
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2092
Nyckelord
Chlamydia trachomatis, 2-pyridone, small molecules, KSK213, Structure-Activity Relationships (SAR), antibiotic resistance, target identification, transcription, RNA, progeny, infectivity
Nationell ämneskategori
Infektionsmedicin Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) Läkemedelskemi Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-174666 (URN)978-91-7855-340-2 (ISBN)978-91-7855-339-6 (ISBN)
Disputation
2020-09-25, Triple Helix, University management building, Umeå, 13:00 (Engelska)
Opponent
Handledare
Anmärkning

Additional appendix only available in printed version, as it contains specific methods that we want to publish in the future. 

Tillgänglig från: 2020-09-04 Skapad: 2020-09-01 Senast uppdaterad: 2020-09-02Bibliografiskt granskad

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Kulén, MartinaNúñez-Otero, CarlosCairns, Andrew G.Silver, JimLindgren, Anders E. G.Andersson, Emma K.Singh, PardeepVielfort, KatarinaBahnan, WaelGood, James A. D.Bergström, SvenGylfe, ÅsaAlmqvist, Fredrik

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Kulén, MartinaNúñez-Otero, CarlosCairns, Andrew G.Silver, JimLindgren, Anders E. G.Andersson, Emma K.Singh, PardeepVielfort, KatarinaBahnan, WaelGood, James A. D.Bergström, SvenGylfe, ÅsaAlmqvist, Fredrik
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Kemiska institutionenUmeå Centre for Microbial Research (UCMR)Molekylär Infektionsmedicin, Sverige (MIMS)Institutionen för klinisk mikrobiologiInstitutionen för molekylärbiologi (Medicinska fakulteten)
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